plozasiran (ARO-APOC3) / Arrowhead - LARVOL DELTA

Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • Pancreatitis

Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. (PubMed, N Engl J Med) - No abstract available

Journal • Pancreatitis

EFFECT OF PLOZASIRAN TARGETING APOC3 ON LIPOPROTEIN PARTICLE NUMBER AND SIZE MEASURED BY NMR IN PATIENTS WITH HYPERTRIGLYCERIDEMIA (HTG) - Christie M. Ballantyne (ACC 2025) - "PZN induces APOC3 decreases and favorable quantitative and qualitative changes in lipoproteins as assessed by NMR in HTG patients. PZN reduces TRL-P by ~50%, shifts LDL to larger particles, and increases HDL-P concentration. While high-potency TRL-lowering therapies can sometimes lead to an overall LDL-C increase, PZN does not increase LDL-P but does shift LDL particle size distribution from sdLDL towards larger sizes."

Clinical • Dyslipidemia • Hypertriglyceridemia • Mixed Hyperlipidemia • Severe Hypertriglyceridemia

Plozasiran: "Plozasiran demonstrated potent and durable reductions of atherogenic lipoproteins in HTG populations"; Hypertriglyceridemia (Arrowhead) - Effect of Plozasiran Targeting APOC3 on Lipoprotein Particle Number and Size Measured by NMR in Patients with Hypertriglyceridemia

P2 data • Hypertriglyceridemia • Metabolic Disorders

Safety and efficacy of antisense oligonucleotides on triglyceride, apolipoprotein C-III, and other lipid parameters levels in hypertriglyceridemia; a network meta-analysis of randomized controlled trials. (PubMed, Lipids Health Dis) - "APOC3 antisense oligonucleotide inhibitors effectively reduced triglyceride and APOC3 levels in hypertriglyceridemia with an acceptable safety profile. However, the results should be interpreted cautiously due to the small sample size. Further research is needed to confirm the beneficial effects of APOC3 inhibitors and show strong evidence of the impact of each regimen."

Clinical • Journal • Retrospective data • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • APOC3

Apolipoprotein C-III inhibitors for the treatment of hypertriglyceridemia: A meta-analysis of randomized controlled trials. (PubMed, Metabolism) - "APOC-III inhibitors improve TG levels and other lipid panel parameters, as well as reduce episodes of acute pancreatitis in patients with primary and secondary hypertriglyceridemia."

Journal • Retrospective data • Atherosclerosis • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Pancreatitis • Severe Hypertriglyceridemia

Familial chylomicronemia syndrome and treatments to target hepatic APOC3 mRNA. (PubMed, Atherosclerosis) - "Reduced TG, lower rates of acute pancreatitis events, and similar proportions of adverse events in placebo and treated patients were recently demonstrated in placebo-controlled phase 3 trials of patients with FCS treated with olezarsen in Balance and with plozasiran in PALISADE. This review discusses causes and consequences of FCS and the rationale and progress made in developing APOC3 RNA-targeted therapeutics for the treatment of FCS."

Journal • Review • Dyslipidemia • Familial Chylomicronemia Syndrome • Hypertriglyceridemia • Pancreatitis • APOC3 • LPL

Study of VSA001 Injection in Chinese Healthy Adult Volunteers (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Visirna Therapeutics HK Limited | Not yet recruiting ➔ Completed

Trial completion

Effect of Targeting apoC-III with Plozasiran on Lipoprotein Particle Size and Number in Hypertriglyceridemia. (PubMed, J Am Coll Cardiol) - "Plozasiran induced reductions in apoC-III and showed potentially favorable quantitative and qualitative changes in lipoproteins as assessed by NMR in patients with hypertriglyceridemia and mixed hyperlipidemia. Plozasiran reduced TRL-P by ∼50%, shifted LDL to larger particles, and modestly increased HDL-P concentration. While high-potency TRL-lowering therapies can lead to an overall LDL-C increase, plozasiran did not increase LDL-P or apoB but shifted LDL particle size distribution from small dense LDL towards larger sizes. The ∼50% reduction in TRL-P with no increase in apoB and possibly beneficial qualitative changes in LDL suggests the potential of plozasiran to lower cardiovascular risk, which may be evaluated in a prospective outcomes trial."

Journal • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Mixed Hyperlipidemia • Severe Hypertriglyceridemia • APOB

The first-of-its-kind APOC3 siRNA was successfully tested in China in Phase III, requiring only one dose every three months [Google translation] (vbdata.cn) - P3 | N=30 | NCT05902598 | Sponsor: Visirna Therapeutics HK Limited | "Viagene announced that VSA001 injection (Pleslan sodium) has obtained positive top-line data in the Phase III clinical trial (CTR20231418/NCT05902598) of patients with familial chylomicronemia syndrome (FCS) in China, successfully reaching the primary efficacy endpoint and all key secondary endpoints....A total of 37 FCS patients were randomly assigned to receive subcutaneous injections of VSA001 25 mg, 50 mg or placebo every 3 months for 12 months, aiming to evaluate the efficacy and safety of VSA001 in adult patients with FCS in China. The primary endpoint of the study was the median percentage change in fasting serum triglyceride levels from baseline at month 10 compared with the placebo group."

P3 data: top line • Familial Chylomicronemia Syndrome

SHASTA-5: Study of Plozasiran in Adults With Severe Hypertriglyceridemia at Risk of Acute Pancreatitis (clinicaltrials.gov) - P3 | N=140 | Not yet recruiting | Sponsor: Arrowhead Pharmaceuticals

New P3 trial • Dyslipidemia • Hypertriglyceridemia • Pancreatitis • Severe Hypertriglyceridemia

A Phase 3 Study of VSA001 in Chinese Adults with Familial Chylomicronemia Syndrome (clinicaltrials.gov) - P3 | N=30 | Active, not recruiting | Sponsor: Visirna Therapeutics HK Limited | Not yet recruiting ➔ Active, not recruiting | Trial completion date: Dec 2025 ➔ Jul 2026

Enrollment closed • Trial completion date • Familial Chylomicronemia Syndrome • APOA5 • LPL

Targeting apolipoprotein C-III: a game changer for pancreatitis prevention in severe hypertriglyceridemia. (PubMed, Curr Opin Endocrinol Diabetes Obes) - "SHTG is a high-burden metabolic disorder that is associated with a significantly increased incidence and severity of acute pancreatitis. Traditional lifestyle interventions and conventional therapies, including fibrates and n-3 fatty acids, often provide only modest reductions in triglycerides and fail to prevent sHTG-associated acute pancreatitis. The emergence of novel and targeted RNA-therapies represents a potential breakthrough in the management of sHTG and acute pancreatitis prevention."

Journal • Dyslipidemia • Hypertriglyceridemia • Metabolic Disorders • Pancreatitis • Severe Hypertriglyceridemia

Current and Emerging Treatment Options for Hypertriglyceridemia: State-of-the-Art Review. (PubMed, Pharmaceuticals (Basel)) - "Among apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran appear to be safer alternatives for volanesorsen regarding the risk of drug-induced thrombocytopenia in patients with FCS or severe HTG. After the failure of vupanorsen, a new angiopoietin-like protein 3 (ANGPTL3) inhibitor, zodasiran, demonstrated the potential to decrease TG levels in patients with moderate HTG. Meanwhile, the fibroblast growth factor 21 (FGF21) analog, pegozafermin, became another candidate for the treatment of severe HTG. This comprehensive review outlines pharmacological targets in TG-rich lipoprotein metabolism, discusses international guidelines, and summarizes the latest evidence from clinical trials to provide insight into the current and emerging treatment options for primary HTG."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Chylomicronemia Syndrome • Hematological Disorders • Hypertriglyceridemia • Metabolic Disorders • Pancreatitis • Severe Hypertriglyceridemia • Thrombocytopenia • ANGPTL3 • FGF21

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2024 American Heart Association Scientific Sessions. (PubMed, Curr Atheroscler Rep) - "Included studies assessed effects of intensive blood pressure control in patients with type 2 diabetes (BPROAD); decision support system for physicians to optimize early lipid lowering therapies after acute coronary syndrome (ZODIAC); efficacy and safety of zerlasiran, a short interfering RNA targeting lipoprotein(a) (ALPACAR); efficacy and safety of muvalaplin an oral disrupter of the assembly of lipoprotein(a) particles (KRAKEN); safety and efficacy of obicetrapib in patients with heterozygous familial hypercholesterolemia (BROOKLYN); efficacy and safety of lerodalcibep, a third generation PCSK9 inhibitor in heterozygous familial hypercholesterolemia subjects (LIBerate-HeFH_OLE); personalized app-based coaching to improve physical activity in patients with HFpEF compared to standard care (MyoMobile); semaglutide to improve cardiovascular outcomes in patients with a history of coronary artery bypass surgery and overweight or obesity (the SELECT trial); efficacy and..."

Journal • Review • Acute Coronary Syndrome • Cardiovascular • Diabetes • Dyslipidemia • Familial Chylomicronemia Syndrome • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders • Obesity • Pancreatitis • Type 2 Diabetes Mellitus

Arrowhead Pharmaceuticals Reports Fiscal 2025 First Quarter Results (Businesswire) - "The company is now well positioned for growth with plans for an independent commercial launch in 2025 and the potential for multiple partner launches over the coming few years. Phase 3 studies of plozasiran in severe hypertriglyceridemia are on pace to be fully enrolled in 2025 with potential study completion in 2026....Arrowhead is currently funded into 2028 with further cash runway potential with multiple wholly owned candidates providing opportunities for additional partnerships...PALISADE successfully met its primary endpoint and all multiplicity-controlled key secondary endpoints, including statistically significant reductions in triglycerides, apolipoprotein C-III, and the incidence of acute pancreatitis. The FDA provided a Prescription Drug User Fee Act (PDUFA) action date of November 18, 2025, and indicated it is not currently planning to hold an advisory committee meeting."

Commercial • Launch • PDUFA • Familial Chylomicronemia Syndrome • Severe Hypertriglyceridemia

Novel RNA-Based Therapies in the Management of Dyslipidemias. (PubMed, Int J Mol Sci) - "This article discusses the latest data from completed and ongoing trials on RNA therapies for dyslipidemia, including inclisiran, pelacarsen, olpasiran, zerlasiran, lepodisiran, volanesorsen, olezarsen, plozasiran, zodasiran, and solbinsiran. Each therapy targets specific molecules while also significantly impacting other lipid parameters. The promising results of these trials indicate potential improvements in lipid therapy and cardiovascular risk reduction, with ongoing studies expected to further refine the role of the novel RNA-based agents in effective lipid management."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • ANGPTL3

Plozasiran: Completion of enrolment of P3 SHASTA-3 trial (NCT06347003) for severe hypertriglyceridemia in 2025 (Arrowhead) - Q4 2024 Results: Completion of enrolment of P3 SHASTA-4 trial (NCT06347016) for severe hypertriglyceridemia in 2025

Enrollment status • Hypertriglyceridemia • Metabolic Disorders

SHASTA-10: Long-Term Safety and Efficacy of Plozasiran in Adults With Hypertriglyceridemia (clinicaltrials.gov) - P3 | N=840 | Not yet recruiting | Sponsor: Arrowhead Pharmaceuticals

New P3 trial • Dyslipidemia • Hypertriglyceridemia

Molecular Therapeutics in Development to Treat Hyperlipoproteinemia. (PubMed, Mol Diagn Ther) - "Inhibition of APOC3 messenger RNA expression by olezarsen and plozasiran significantly lowers plasma triglyceride levels and markedly reduces pancreatitis risk in patients with familial chylomicronemia syndrome. Finally, angiopoietin-like protein 3 inhibition by the monoclonal antibody evinacumab has transformed management of patients with homozygous familial hypercholesterolemia. Together, these novel agents expand the therapeutic cache, offering personalized lipid-lowering strategies for high-risk patients with hyperlipoproteinemia, improving clinical outcomes and addressing previously unmet medical needs."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Chylomicronemia Syndrome • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • Pancreatitis

Treatment Protocol of Plozasiran in Adults With FCS (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Arrowhead Pharmaceuticals

New trial • Familial Chylomicronemia Syndrome

Arrowhead Pharmaceuticals Announces Acceptance of New Drug Application by U.S. FDA of Plozasiran for the Treatment of Familial Chylomicronemia Syndrome (Businesswire) - "Arrowhead Pharmaceuticals...announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for investigational plozasiran for the treatment of familial chylomicronemia syndrome (FCS), a severe and rare genetic disease. The FDA provided a Prescription Drug User Fee Act (PDUFA) action date of November 18, 2025, and indicated it is not currently planning to hold an advisory committee meeting. Arrowhead also intends to submit applications for approval of investigational plozasiran for the treatment of patients with FCS to additional regulatory authorities in 2025....The clinical basis of the NDA submission is comprised of the positive findings in the Phase 3 PALISADE study with supportive confirmatory evidence from the Phase 2 clinical studies of the SUMMIT Program."

FDA filing • Filing • PDUFA • Familial Chylomicronemia Syndrome

Exploring emerging pharmacotherapies for type 2 diabetes patients with hypertriglyceridemia. (PubMed, Expert Opin Pharmacother) - "These were identified by a PubMed search and mainly focus on pemafibrate and the drugs targeting apolipoprotein C3 (apoC3) and angiopoietin-like 3 (ANGPTL3)...Inhibitors of apoC3 are effective in reducing triglycerides even in familial chylomicronaemia syndrome and olezarsen and plozasiran in this group are being studied in patients with combined hyperlipidemia. The ANGPTL3 inhibitor evinacumab has been approved for homozygous familial hypercholesterolemia and other ANGPTL3 inhibitors may prove be useful to reduce triglycerides in T2D."

Journal • Review • Cardiovascular • Diabetes • Dyslipidemia • Familial Chylomicronemia Syndrome • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Hypertriglyceridemia • Metabolic Disorders • Type 2 Diabetes Mellitus • ANGPTL3

Plozasiran: “10, 25 or 50 mg of plozasiran under blinded conditions produced mean reductions in triglycerides up to -64% (MUIR) and up to -74% (SHASTA-2), 12 weeks (trough) after the second dose”; Hypertriglyceridemia (Arrowhead) - 21st Global CVCT Forum: “Corresponding trough reductions in the extension were maintained up to -73% (MUIR) and -86% (SHASTA-2) through 15 months follow-up”

P2 data • Hypertriglyceridemia • Metabolic Disorders

Plozasiran: “Plozasiran substantially reduced triglycerides in patients with persistent chylomicronemia (FCS or FCS-like syndrome) and over half achieved TG treatment goals (75% < 880 mg/dL, 50% < 500 mg/dL), invariant of FCS genotype”; Familial chylomicronemia syndrome (Arrowhead) - 21st Global CVCT Forum: “Reductions in TGs and APOC3 were apparent at 1 month and sustained thereafter over 12 months with comparable efficacy in genetically and clinically-defined patients”

P3 data • Familial Chylomicronemia Syndrome • Metabolic Disorders